Biliary atresia, also known as extrahepatic ductopenia and progressive obliterative cholangiopathy, is a childhood disease of the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

in which one or more

bile duct A bile duct is any of a number of long tube-like structures that carry bile, and is present in most vertebrates. Bile is required for the digestion of food and is secreted by the liver into passages that carry bile toward the hepatic duct. It ...

s are abnormally narrow, blocked, or absent. It can be

congenital A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...

or acquired. It has an incidence of one in 10,000–15,000 live births in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territorie ...

, and a

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

of one in 16,700 in the

British Isles The British Isles are a group of islands in the North Atlantic Ocean off the north-western coast of continental Europe, consisting of the islands of Great Britain, Ireland, the Isle of Man, the Inner and Outer Hebrides, the Northern Isles, ...

. Biliary atresia is most common in

East Asia East Asia is the eastern region of Asia, which is defined in both geographical and ethno-cultural terms. The modern states of East Asia include China, Japan, Mongolia, North Korea, South Korea, and Taiwan. China, North Korea, South Korea and ...

, with a frequency of one in 5,000. The cause of biliary atresia in Egyptian infants has been proven to be as a result of

aflatoxin Aflatoxins are various poisonous carcinogens and mutagens that are produced by certain molds, particularly ''Aspergillus'' species. The fungi grow in soil, decaying vegetation and various staple foodstuffs and commodities such as hay, sweetcorn ...

induced cholangiopathy acquired prenatally in infants who have glutathione S transferase M1 deficiency. The biliary atresia phenotype caused by congenital aflatoxicosis in GST M1 deficient neonates is named Kotb disease. Syndromic biliary atresia (e.g. Biliary Atresia Splenic Malformation (BASM)) has been associated with certain genes (e.g. Polycystic Kidney Disease 1 Like 1 - PKD1L1), and some infants with isolated biliary atresia may arise as a result of an

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". P ...

inflammatory response, possibly due to a

viral infection A viral disease (or viral infection) occurs when an organism's body is invaded by pathogenic viruses, and infectious virus particles (virions) attach to and enter susceptible cells. Structural Characteristics Basic structural characteristics, s ...

of the liver soon after birth. In animals plant toxins have been shown to cause biliary atresia. The only effective treatments are operations such as the

Kasai procedure A hepatoportoenterostomy or Kasai portoenterostomy is a surgical treatment performed on infants with Type IVb choledochal cyst and biliary atresia to allow for bile drainage. In these infants, the bile is not able to drain normally from the smal ...

and liver transplantation.

Signs and symptoms

Initially, the symptoms of biliary atresia are indistinguishable from those of

neonatal jaundice Neonatal jaundice is a yellowish discoloration of the white part of the eyes and skin in a newborn baby due to high bilirubin levels. Other symptoms may include excess sleepiness or poor feeding. Complications may include seizures, cerebral pal ...

, a usually harmless condition commonly seen in infants. However, infants with biliary atresia develop progressive conjugated jaundice, pale white stools, and dark urine. Some infants fail to thrive as there will be a degree of fat and fat-soluble vitamin malabsorption (e.g. Vitamin K). This may cause a bleeding tendency. Eventually, and usually after 2 months,

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

with portal hypertension will develop. If left untreated, biliary atresia can lead to liver failure. Unlike other forms of

jaundice Jaundice, also known as icterus, is a yellowish or greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving abnormal heme meta ...

, however, biliary-atresia-related cholestasis mostly does not result in

kernicterus Kernicterus is a bilirubin-induced brain dysfunction. The term was coined in 1904 by Christian Georg Schmorl. Bilirubin is a naturally occurring substance in the body of humans and many other animals, but it is neurotoxic when its concentratio ...

, a form of brain damage resulting from liver dysfunction. This is because in biliary atresia, the liver, although diseased, is still able to conjugate

bilirubin Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...

, and conjugated bilirubin is unable to cross the blood–brain barrier.

Causes

The cause of biliary atresia in most infants is not fully understood and it is well possible that a number of factors may play a role, but especially maternal

rotavirus ''Rotavirus'' is a genus of double-stranded RNA viruses in the family ''Reoviridae''. Rotaviruses are the most common cause of diarrhoeal disease among infants and young children. Nearly every child in the world is infected with a rotavirus a ...

infection during pregnancy and subsequent transmission of the virus to the child resulting in infection of the biliary epithelium and subsequent occluding fibrosis may be important in this respect. Some cases may relate to infection with other viruses (including

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...

) as well, for instance infection with the hepatotropic virus reovirus 3 has been proposed and congenital

cytomegalovirus ''Cytomegalovirus'' (''CMV'') (from ''cyto-'' 'cell' via Greek - 'container' + 'big, megalo-' + -''virus'' via Latin 'poison') is a genus of viruses in the order ''Herpesvirales'', in the family ''Herpesviridae'', in the subfamily ''Betaherpe ...

infection, as well. In addition autoimmune processes may contribute to pathogenesis in some cases as well. However, with regard to these alternative causation the experimental evidence remains rather weak.

Genetics

An association between biliary atresia and the ''

ADD3 Gamma-adducin is a protein that in humans is encoded by the ''ADD3'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' o ...

'' gene was first detected in

Chinese Chinese can refer to: * Something related to China * Chinese people, people of Chinese nationality, citizenship, and/or ethnicity **''Zhonghua minzu'', the supra-ethnic concept of the Chinese nation ** List of ethnic groups in China, people of ...

populations through a

genome-wide association study In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of Single-nucleotide polymorphism, genetic variants in different i ...

, and was confirmed in

Thai Thai or THAI may refer to: * Of or from Thailand, a country in Southeast Asia ** Thai people, the dominant ethnic group of Thailand ** Thai language, a Tai-Kadai language spoken mainly in and around Thailand *** Thai script *** Thai (Unicode block ...

Asians and Caucasians. A possible association with deletion of the gene ''

GPC1 Glypican-1 (GPC1) is a protein that in humans is encoded by the ''GPC1'' gene. GPC1 is encoded by human ''GPC1'' gene located at 2q37.3. GPC1 contains 558 amino acids with three predicted heparan sulfate chains. Function Cell surface heparan su ...

'', which encodes a glypican 1-a

heparan sulfate Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan (HSPG, i.e. Heparan Sulfate ProteoGlycan) in which two or three HS chains are attached in close proximity to cell surface or extracellular ma ...

proteoglycan, has been reported. This gene is located on the long arm of

chromosome 2 Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost e ...

(2q37) and is involved in the regulation of inflammation and the

Hedgehog A hedgehog is a spiny mammal of the subfamily Erinaceinae, in the eulipotyphlan family Erinaceidae. There are seventeen species of hedgehog in five genera found throughout parts of Europe, Asia, and Africa, and in New Zealand by introducti ...

gene. Egyptian infants with biliary atresia were found to have null ''GSTM1'' genotype while all their mothers were heterozygous for ''GSTM1''. Thus these infants may be protected in utero by their maternal detoxification system, yet once born they cannot handle the detoxification of an aflatoxin load.

Toxins

Some cases of biliary atresia may result from exposure to aflatoxin B1, and to a lesser extent aflatoxin B2 during late pregnancy. Intact maternal detoxification protects baby during intrauterine life, yet after delivery, the baby struggles with the aflatoxin in its blood and liver. Moreover, the baby feeds aflatoxin M₁ from its mom, as aflatoxin M₁ is the detoxification product of aflatoxin B1. It is a milder toxin that causes cholangitis in the baby. There are isolated examples of biliary atresia in animals. For instance, lambs born to sheep grazing on land contaminated with a weed ( Red Crumbweed) developed biliary atresia at certain times. The plants were later found to contain a toxin, now called biliatresone Studies are ongoing to determine whether there is a link between human cases of biliary atresia and toxins such as biliatresone. There are some indications that a metabolite of certain human gut bacteria may be similar to biliatresone.

Pathophysiology

There are three main types of extra-hepatic biliary atresia: * Type I: Atresia is restricted to the common bile duct. * Type II: Atresia of the common hepatic duct. * Type III: Atresia involves the most proximal part of the bile ducts (>95% of all cases). In approximately 10% of cases, other anomalies may be associated with biliary atresia. The most common of these syndromic forms is BASM and might include heart lesions,

polysplenia Polysplenia is a congenital disease manifested by multiple small accessory spleens, rather than a single, full-sized, normal spleen. Polysplenia sometimes occurs alone, but it is often accompanied by other developmental abnormalities. Condition ...

situs inversus Situs inversus (also called situs transversus or oppositus) is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement of internal organs is known as situs solitus. Al ...

, absent

venae cavae In anatomy, the venae cavae (; singular: vena cava ; ) are two large veins (great vessels) that return deoxygenated blood from the body into the heart. In humans they are the superior vena cava and the inferior vena cava, and both empty into the ...

, and a preduodenal

portal vein The portal vein or hepatic portal vein (HPV) is a blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver. This blood contains nutrients and toxins extracted from digested contents. Approxima ...

. Progressive cirrhosis is associated with signs and symptoms of portal hypertension, such as esophagogastric varix bleeding,

hypersplenism Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulati ...

hepatorenal syndrome Hepatorenal syndrome (often abbreviated HRS) is a life-threatening medical condition that consists of rapid deterioration in kidney function in individuals with cirrhosis or fulminant liver failure. HRS is usually fatal unless a liver transplan ...

, and

hepatopulmonary syndrome In medicine, hepatopulmonary syndrome is a syndrome of shortness of breath and hypoxemia (low oxygen levels in the blood of the arteries) caused by vasodilation (broadening of the blood vessels) in the lungs of patients with liver disease. Dyspnea ...

. In an Egyptian study, abnormally high levels of

aflatoxin B1 Aflatoxin B1 is an aflatoxin produced by ''Aspergillus flavus'' and '' A. parasiticus''. It is a very potent carcinogen with a TD50 3.2 μg/kg/day in rats. This carcinogenic potency varies across species with some, such as rats and monkeys, seem ...

and to a lesser extent aflatoxin B2 was found in liver tissue and blood of all neonates with biliary atresia. Aflatoxins may cause extensive damage to the hepatocytes leading to hepatitis and damage to bile ducts causing inflammation, adhesions and final obstruction of bile ducts. The affected neonates have a genetic detoxification defect that does not allow them to detoxify these aflatoxins timely or effectively. The babies have homozygous deficiency of glutathione S transferase (GST) M1. The aflatoxin damaged liver cells and bile duct cells are removed by

neutrophil elastase Neutrophil elastase (, ''leukocyte elastase'', ''ELANE'', ''ELA2'', ''elastase 2'', ''neutrophil'', ''elaszym'', ''serine elastase'', subtype ''human leukocyte elastase (HLE)'') is a serine proteinase in the same family as chymotrypsin and has br ...

and by involvement of immune system mediators such as CCL-2 or MCP-1, tumor necrosis factor (TNF), interleukin-6 (IL-6),

TGF-beta Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...

, endothelin (ET), and nitric oxide (NO). Among these, TGF-beta is the most important pro-fibrogenic cytokine that can be seen in progressive cirrhosis. The cascade of immune involvement to remove damaged hepatocytes and cholangiocytes ushers regeneration. Yet in infants with biliary atresia regeneration is defective, and results in

, as these infants have disrupted

p53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...

and disrupted GSTPi. p53 and GSTPi are responsible for DNA fidelity at regeneration. Hence, these infants get accelerated cirrhosis and march to portal hypertension.

Diagnosis

Diagnosis is made by an assessment of history, physical examination in conjunction with

blood tests A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose test or a cholester ...

, a

liver biopsy Liver biopsy is the biopsy (removal of a small sample of tissue) from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment. Medica ...

, and ultrasound scans

imaging Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image). Imaging technology is the application of materials and methods to create, preserve, or duplicate images. ...

and is prompted by prolonged or persistent jaundice, with abnormalities in liver function tests.

Ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...

or other forms of imaging such as radio-isotope liver scans can also be used but final confirmation is usually only reached at the time of exploratory surgery.

Differential diagnoses

The

differential diagnoses In healthcare, a differential diagnosis (abbreviated DDx) is a method of analysis of a patient's history and physical examination to arrive at the correct diagnosis. It involves distinguishing a particular disease or condition from others that p ...

are extensive and include:

Alagille syndrome Alagille syndrome is a genetic disorder that affects primarily the liver and the heart. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and t ...

, alpha-1-antitrypsin deficiency, Byler disease (

progressive familial intrahepatic cholestasis Progressive familial intrahepatic cholestasis (PFIC) is a group of familial cholestatic conditions caused by defects in biliary epithelial transporters. The clinical presentation usually occurs first in childhood with progressive cholestasis. Thi ...

Caroli disease Caroli disease (communicating cavernous ectasia, or congenital cystic dilatation of the intrahepatic biliary tree) is a rare inherited disorder characterized by cystic dilatation (or ectasia) of the bile ducts within the liver. There are two patter ...

, choledochal cyst,

cholestasis Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignan ...

, congenital

disease, congenital

herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...

infection,

congenital rubella Congenital rubella syndrome (CRS) can occur in a developing fetus of a pregnant woman who has contracted rubella, usually in the first trimester. If infection occurs 0–28 days before conception, the infant has a 43% risk of being affected. If t ...

congenital syphilis Congenital syphilis is syphilis present ''in utero'' and at birth, and occurs when a child is born to a mother with syphilis. Untreated early syphilis infections results in a high risk of poor pregnancy outcomes, including saddle nose, lower ext ...

congenital toxoplasmosis Toxoplasmosis is a parasitic disease caused by '' Toxoplasma gondii'', an apicomplexan. Infections with toxoplasmosis are associated with a variety of neuropsychiatric and behavioral conditions. Occasionally, people may have a few weeks or months ...

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

galactosemia Galactosemia (British galactosaemia, from Greek γαλακτόζη + αίμα, meaning galactose + blood, accumulation of galactose in blood) is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galacto ...

, idiopathic

neonatal hepatitis Neonatal hepatitis refers to many forms of liver dysfunction that affects fetuses and neonates. It is most often caused by viruses or metabolic diseases, and many cases are of an unknown cause. Signs and symptoms The infant with neonatal hepatiti ...

, lipid storage disorders, neonatal

hemochromatosis Iron overload or hemochromatosis (also spelled ''haemochromatosis'' in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage. The most important causes are hereditary haemochromatosi ...

, and

total parenteral nutrition Parenteral nutrition (PN) is the feeding of nutritional products to a person intravenously, bypassing the usual process of eating and digestion. The products are made by pharmaceutical compounding companies. The person receives a nutritional mix ...

-associated cholestasis.

Treatment

Most (>95%) infants with biliary atresia will undergo an operation designed to retain and salvage the native liver, restore bile flow, and reduce the level of jaundice. This is known as the Kasai procedure (after

Morio Kasai Morio Kasai (; September 29, 1922 – December 8, 2008) was a Japanese surgeon who had a strong interest in pediatric surgery. While Kasai went into practice at a time when pediatric surgery was not an established subspecialty, much of his clinica ...

, the Japanese surgeon who first developed the technique) or

hepatoportoenterostomy A hepatoportoenterostomy or Kasai portoenterostomy is a surgical treatment performed on infants with Type IVb choledochal cyst and biliary atresia to allow for bile drainage. In these infants, the bile is not able to drain normally from the small ...

. Although the procedure is not thought of as curative, it may relieve jaundice and stop liver fibrosis, allowing normal growth and development. Published series from Japan, North America, and the UK show that bilirubin levels will fall to normal values in about 50-55% of infants, allowing 40-50% to retain their own liver to reach the age of 5 and 10 years (and beyond). Liver transplantation is an option for those children whose liver function and symptoms fail to respond to a Kasai operation. Recent large-scale studies by Davenport et al. (''Annals of Surgery'', 2008) show that the age of the patient is not an absolute clinical factor affecting

prognosis Prognosis (Greek: πρόγνωσις "fore-knowing, foreseeing") is a medical term for predicting the likely or expected development of a disease, including whether the signs and symptoms will improve or worsen (and how quickly) or remain stabl ...

. The influence of age differs according to the disease etiology—i.e., whether biliary atresia is isolated, cystic (CBA), or accompanied by splenic malformation (BASM). It is widely accepted that

corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...

treatment after a Kasai operation, with or without

choleretic Choleretics are substances that increase the volume of secretion of bile from the liver as well as the amount of solids secreted. See also * Cholekinetic * Hydrocholeretic Hydrocholeretics are substances that increase the volume of secretion of bi ...

s and

antibiotics An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...

, has a beneficial effect on postoperative bile flow and can clear jaundice, but the dosing and duration of the ideal steroid protocol are controversial. Furthermore, it has been observed in many retrospective longitudinal studies that corticosteroid treatment does not seem to prolong survival of the native liver or transplant-free survival.

Epidemiology

Biliary atresia seems to affect females slightly more often than males, and Asians and African Americans more often than Caucasians. It is common for only one child in a pair of twins or within the same family to have the condition. There seems to be no link to medications or immunizations given immediately before or during pregnancy. Diabetes during pregnancy particularly during the first trimester seems to predispose to a number of distinct congenital abnormalities in the infant such as sacral agenesis, transposition of the great vessels and the syndromic form of biliary atresia.

References

External links

{{Congenital malformations and deformations of digestive system Biliary tract disorders Hepatology Congenital disorders of digestive system Rare diseases Articles containing video clips